A free energy decomposition scheme based on the MM-PBSA approach is presented and used to identify interaction hot-spots in biomolecular complexes. The calculations identify protein amino acids that make important contributions to the interaction energy of the complexes. Small structural variations on the energetics of binding are accounted for through the use of multiple conformations. We also define the concept of “efficient amino acids” which can provide an assessment of the binding potential of a particular hot spot interaction. This information, in turn, can be useful in the rational design of small molecules that interfere with protein-protein binding. Applications to different protein-protein and protein-ligand complexes are presented. The work shows that a free energy decomposition scheme can be employed to identify regions of a biomolecular complex that could be subsequently targeted by small molecules inhibitors. Applications of the method to ligand recognition by nuclear receptors also underlines general principles of molecular recognition that are useful for ligand design.

• Legal notice:
  

  Copyright (c) Pielaszek Research, all rights reserved.
  The above materials, including auxiliary resources, are subject to Publisher's copyright and the Author(s) intellectual rights. Without limiting Author(s) rights under respective Copyright Transfer Agreement, no part of the above documents may be reproduced without the express written permission of Pielaszek Research, the Publisher. Express permission from the Author(s) is required to use the above materials for academic purposes, such as lectures or scientific presentations.
  In every case, proper references including Author(s) name(s) and URL of this webpage: https://science24.com/paper/15987 must be provided.